Objective: Do single NPC1 or NPC2 mutation also predispose to late-onset neurodegeneration, e. g. PD or dementia?

Background: Niemann-Pick type C (NPC) is an autosomal recessive lysosomal storage disorder (LSD) with clinical and pathophysiological similarities to Gaucher disease (GD). Heterozygous mutations associated with GD are the strongest risk factor for late-onset Parkinson’s disease (PD). It remains unclear in how far NPC heterozygosity are associated with a similar risk

Methods: 32 NPC heterozygotes with NPC1 mutations from European and Middle Eastern countries and 36 heatlhy subjects were studied. The test battery contained neurological assessment with video recording, blood analysis, standardized neuropsychological assessment using the CERAD battery, smell testing, video-oculography (VOG), examination of colour vision and optical coherence tomography (OCT), abdominal ultrasound, purdue pegboard test to evaluate the visuo-manual coordination; lumbar puncture to assess for the presence of markers of neurodegeneration and 18[FDG]-PET examination of brain metabolism.

Results: 3 heterozygotes had abnormal chitotriosidase activity levels. 12 out of 17 heterozygotes demonstrated focal neurological deficits, such as increased muscle tone, cerebellar ataxia signs or reduced arm swing during walking; 2 subjects demonstrated impaired smell function. Four scored abnormal on the REM sleep bevaiour scale. Hepatosplenomegaly was observed in 5 out of 12 heterozygotes. OCT showed no definite features of retinal degeneration pattern (preliminary analysis), i.e. pRNFL values and inner retinal layers were within normal limits compared to age- and sex-matched healthy controls. Cognitive deficits and FDG PET changes were also present in a subset.

Conclusions: NPC heterozygosity is associated with various neurological and other medical deficits and may be a risk factor for late-onset neurodegeneration.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/does-niemann-pick-type-c-heterozygosity-predispose-to-late-onset-neurodegeneration/